Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models. Experimental Design: The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models. Results: The IC 50 of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor^induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate^induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells.Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line.When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/ 2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday. Conclusions: ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.Excessive growth factor signaling leads to unregulated growth that can contribute to the pathogenesis of human cancer. The signaling cascade is initiated by the binding of peptide growth factors to their tyrosine kinase receptors at the plasma membrane. The receptor kinases are activated and through the recruitment of the growth factor receptor binding protein 2/son of sevenless complex to autophosphorylated sites on the receptors, the G protein Ras is induced to its active GTP-bound state. Ras recruits the serine/threonine kinase Raf to the plasma membrane, where it is then able to phosphorylate and activate mitogen-activated protein kinase kinases (MEK) 1 and 2, which are dual specificity protein kinases that phosphorylate serine/ threonine and tyrosine residues. The MEK kinases in turn phosphorylate and activate their only currently known substrates, extracellular signal-regulated kinases (ERK) 1 and 2. ERK1/2 proteins translocate to the nucleus where they phosphorylate and activate effector proteins and transcription factors, resulting in diverse cellular responses, including proliferation.The overexpression and/or mutation of epidermal growth factor (EGF) receptor (EGFR), erbB2, platelet-derived growth factor receptor, RET, and othe...

Background With the onset of the COVID-19 crisis, many federal agencies relaxed policies regulating opioid use disorder treatment. The impact of these changes has been minimally documented. The abrupt nature of these shifts provides a naturalistic opportunity to examine adaptations for opioid use disorder treatment in primary care. Objective To examine change in medical and behavioral health appointment frequency, visit type, and management of patients with opioid use disorder in response to COVID-19. Design A 14-item survey queried primary care practices that were enrolled in a medications for opioid use disorder statewide expansion project. Survey content focused on changes in service delivery because of COVID-19. The survey was open for 18 days. Participants We surveyed 338 clinicians from 57 primary care clinics located in California, including federally qualified health centers and look-alikes. A representative from all 57 clinics (100%) and 118 staff (34.8% of all staff clinicians) participated in the survey. Main Measures The survey consisted of seven dimensions of practice: medical visits, behavioral health visits, medication management, urine drug screenings, workflow, perceived patient demand, and staff experience. Key Results A total of 52 of 57 (91.2%) primary care clinics reported practice adaptations in response to COVID-19 regulatory changes. Many clinics indicated that both medical (40.4%) and behavioral health visits (53.8%) were now exclusively virtual. Two-thirds (65.4%) of clinics reported increased duration of buprenorphine prescriptions and reduced urine drug screenings (67.3%). The majority (56.1%) of clinics experienced an increase in patient demand for behavioral health services. Over half (56.2%) of clinics described having an easier or unchanged experience retaining patients in care. Conclusions Many adaptations in the primary care approach to patients with opioid use disorder may be temporary reactions to COVID-19. Further evaluation of the impact of these adaptations on patient outcomes is needed to determine whether changes should be maintained post-COVID-19.

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

Conversion therapies are any treatments, including individual talk therapy, behavioral (e.g. aversive stimuli), group therapy or milieu (e.g. “retreats or inpatient treatments” relying on all of the above methods) treatments, which attempt to change an individual's sexual orientation from homosexual to heterosexual. However, these practices have been repudiated by major mental health organizations because of increasing evidence that they are ineffective and may cause harm to patients and their families who fail to change. At present, California, New Jersey, Oregon, Illinois, Vermont, Washington, D.C., and the Canadian Province of Ontario have passed legislation banning conversion therapy for minors and an increasing number of U.S. States are considering similar bans. In April 2015, the Obama administration also called for a ban on conversion therapies for minors. The growing trend toward banning conversion therapies creates challenges for licensing boards and ethics committees, most of which are unfamiliar with the issues raised by complaints against conversion therapists. This paper reviews the history of conversion therapy practices as well as clinical, ethical and research issues they raise. With this information, state licensing boards, ethics committees and other regulatory bodies will be better able to adjudicate complaints from members of the public who have been exposed to conversion therapies.